Relationship Between Laryngomalacia and Sleep-Related Breathing Disorders in Infants with Brief Resolved Unexplained Events

Home , Laryngomalacia, Stridor

www.jpnim.com Open Access eISSN: 2281-0692 Journal of Pediatric and Neonatal Individualized Medicine 2021;10(2):e100207 doi: 10.7363/100207 Received: 2021 Feb 03; revised: 2021 May 04; accepted: 2021 May 09; published online: 2021 Jun 04 Original article Relationship between laryngomalacia and sleep-related breathing disorders in infants with brief resolved unexplained events

Luana Nosetti1, Francesca De Bernardi2, Eleonora Sica3, Patrizia Latorre2, Massimo Agosti4, Paolo Castelnuovo2, Giulia Cocciolo1, Marco Zaffanello5

1Division of Pediatrics, “F. Del Ponte” Hospital, University of Insubria, Varese, Italy 2Department of Otorhinolaryngology, University of Insubria and ASST Sette Laghi, Ospedale di Circolo, Varese, Italy 3PhD Course in Clinical and Experimental Medicine and Medical Humanities, University of Insubria and ASST Sette Laghi, Ospedale di Circolo, Varese, Italy 4Department of Neonatology, NICU and Pediatrics, “F. Del Ponte” Hospital, University of Insubria, Varese, Italy 5Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy

Abstract

Introduction: Brief resolved unexplained events (BRUE) occur during infancy. It is characterized by one or more symptoms, including skin color change, shortness of breath and unresponsiveness. Laryngomalacia is the most frequent cause of stridor in infants and results in the collapse of the supraglottic structures during inspiration and intermittent obstruction of the upper airways. To our knowledge, the relationship between BRUE and laryngomalacia has been little investigated. Methods: The medical records of 448 children (age < 12 months) treated for BRUE between July 2011 and March 2018 and followed up until March 2020 were retrospectively reviewed. Endoscopic evaluation was performed using a flexible fibrolaryngoscope. All patients underwent a brief polysomnography and 24-h cardiorespiratory monitoring. Cardiorespiratory and oxygen saturation monitoring was continued at home; 94% of patients underwent follow-up. Results: Laryngeal fiberoptic endoscopy revealed laryngomalacia in 11% of children with a clinical history of BRUE. Laryngomalacia was associated with obstructive/mixed apnea in 67%. Home cardiorespiratory monitoring showed a gradual reduction in the number of respiratory events during follow- up and complete resolution of laryngomalacia in 88% of patients.

1/8 www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine • vol. 10 • n. 2 • 2021

Conclusions: This is the first report that new term, BRUE, and recommended that the term showed follow-up data from cases of BRUE ALTE no longer be used [3]. High-risk infants with laryngomalacia. The improvement in are younger than 2 months of age, have a history laryngomalacia alone, although not complete, was of prematurity (higher in infants of less than 32 sufficient to improve obstructive events. weeks’ gestation), and a history of more than one event [4]. The Italian guidelines recommend the Keywords use of the term BRUE only when referring to mild, idiopathic cases and the use of the acronym ALTE Laryngomalacia, brief resolved unexplained event, for severe cases that are unexplainable after first obstructive sleep apnea, children. and second level examinations [5]. In 2019 Merritt et al. proposed a tiered approach Corresponding author for clinical evaluation and management of higher risk infants who have experienced BRUE. There Marco Zaffanello, Department of Surgical Sciences, Dentistry, are many potential causes of higher risk BRUE. Gynecology and Pediatrics, Woman & Child Hospital, Building History and physical examination finding, may help 29, Room T1-212, University of Verona, 37126, Verona, Italy; tel.: guide clinicians in identifying specific concerning +39 045 8127121; e-mail: [email protected]. features, one of these is laryngomalacia [4]. Laryngomalacia is the most frequent cause of How to cite stridor in newborns (prevalence 45-75%); it causes collapse of the supraglottic structures during Nosetti L, De Bernardi F, Sica E, Latorre P, Agosti M, Castelnuovo inspiration and obstruction of the upper airways P, Cocciolo G, Zaffanello M. Relationship between laryngomalacia [6-8]. Symptoms generally appear during the first and sleep-related breathing disorders in infants with brief year of life and peak in frequency at 6-8 months resolved unexplained events. J Pediatr Neonat Individual Med. before resolving spontaneously around 12-24 2021;10(2):e100207. doi: 10.7363/100207. months [9]. Laryngeal stridor is due to immaturity of the cartilage scaffold of the larynx. The flaccid Introduction larynx collapses inward over the vocal cords with each breath and causes airway obstruction. Brief resolved unexplained events (BRUE), The clinical manifestation of laryngomalacia is previously termed apparent life-threatening events heterogeneous; it may be asymptomatic or severe, (ALTE) [1], is characterized by one or more leading to insufficient growth, feeding difficulties, symptoms including change in skin color, shortness lung aspiration and obstructive sleep apnea of breath and poor responsiveness. Several (OSA) [10, 11]. Management of severe symptoms potentially dangerous but treatable conditions will entail a multidisciplinary team approach are associated with ALTE. It can be triggered (otolaryngologist [aka ear, nose, and throat – ENT – by a variety of gastrointestinal, neurological, doctor], neonatologist, sleep pediatrician, pediatric respiratory, cardiovascular, metabolic and endo surgeon [for tracheoesophageal anomalies], gastro crine disorders among others [2]. enterologist [for gastroesophageal reflux – GER], BRUE is not a specific diagnosis but rather and geneticist) [7, 10, 12, 13]. Flexible fiberoptic a sudden, short and spontaneously resolved laryngoscopy (FFL) is the procedure of choice for unexplained episode in children under the age the direct visualization of the larynx [10, 14]. of 12 months. The cause of BRUE in infants is To our best knowledge, the relationship between heterogeneous, making diagnosis often difficult on BRUE (and ALTE) events and laryngomalacia has initial presentation [1, 3]. Episodes can sometimes been little investigated to date [15-17]. Okada et resolve quickly and spontaneously without the al. reported only 2 cases of laryngomalacia among need for intervention or may require immediate 69 infants with ALTE over a 10-year period. attention from the observer and intensive care if Laryngomalacia was diagnosed with the aid of a severe. The term BRUE should be applied only laryngoscopy; however, the number of children when the child is asymptomatic and no explanation involved in the survey was not reported [15]. for the episode can be gained from medical Willis et al. performed a 10-year retrospective, history and clinical evaluation [1, 3]. In 2016, the observational study on 1,148 infants with a history subcommittee on apparently threatening events of of ALTE and evaluated in a pediatric ENT service. the American Academy of Pediatrics proposed the The indications for ENT consultation were

2/8 Nosetti • De Bernardi • Sica • Latorre • Agosti • Castelnuovo • Cocciolo • Zaffanello Journal of Pediatric and Neonatal Individualized Medicine • vol. 10 • n. 2 • 2021 www.jpnim.com Open Access gasping, stridor, and aspiration. 471 took part in a ENT evaluation 5-year follow-up (inclusion criteria). Nine of 471 ALTE patients underwent a microlaryngoscopy. ENT evaluation is performed after BRUE Only 3 patients were referred to the pediatric ENT diagnosis and risk stratification with careful history service during initial admission and 6 were seen and physical examination in higher-risk infants. only later in childhood. Finally, only 3 patients If no explanation is identified through the initial were diagnosed with laryngomalacia [16]. In tier evaluation (ECG, hematocrit, blood glucose, another study in infants (n = 128; 0.5-124.2 continuous pulse oximetry), ENT evaluation month-olds), both ALTE and snoring predicted and full polysomnography are indicated. FFL high-airway abnormalities (n = 10, 7%) during is performed by a pediatric otolaryngologist laryngoscopy [17]. (F.D.B.) assisted by a nurse. Small babies are placed in upright position, the nurse holds the Aims baby’s head steady, and the caregiver restrains the child’s arms. Pulse oximetry is used and oxygen To date, laryngomalacia is diagnosed in a and aspiration tubes are on hand. No general select number of children with ALTE or BRUE at sedation is administered. Local anesthesia with initial presentation, and extensive evaluation is not 2% lidocaine is given only in children with a tiny performed. nasal cavity. FFL evaluation is performed using To clarify these issues, we performed a a Pentax flexible fibrolaryngoscope and a Storz- retrospective study reviewing the medical records equipped column with a light source, a camera, of patients presenting at our institution because of a monitor, and a recording system. The portable ALTE or BRUE and, after careful ENT evalua column allows FFL examination in the Neonatal tion, diagnosed with laryngomalacia including Intensive Care Unit when needed. Otherwise, investigation for sleep disordered breathing and all procedures were carried out in a pediatric GER comorbidities. otolaryngology facility in a children’s hospital by certified pediatric advanced life support medical Methods staff, with an emergency room available as a safety precaution. The flexible fiberscope is inserted into Study design the nostril and advanced through the nasal cavity to assess choanal patency. The instrument is then This is a retrospective monocentric obser pushed toward the nasopharynx, the oropharynx, vational study. and the larynx to examine its conformation. There are many classifications of laryngomalacia Study population and all are based on morphological features [18, 19]. Evaluation of the larynx discloses the We reviewed the medical records of children anatomical site of the collapse and identifies (age < 12 months) with ALTE or BRUE evaluated redundant mucosa of the aryepiglottic folds with at our institution between July 2011 and March collapse inward during inspiration (posterolateral), 2018 and followed up until March 2020. short aryepiglottic folds with curled tubular Only patients with FFL-confirmed laryngo epiglottis (complete), and posterior collapse of malacia and with a respiratory sleep study were the epiglottis on inspiration (anterior). Collapse of included in the study. The following clinical data, multiple secondary sites is often present [19, 20]. also extracted from the records, were investiga tion for sleep breathing disorders, respiratory Full polysomnography symptoms and underlined GER. In particular, we included children with ALTE or BRUE at initial All patients underwent a brief 2-h poly presentation who underwent the FFL study and somnography (nap study) with E-Series PSG polysomnography. FFL was also used to investigate Compumedics that included a stable REM phase indirect laryngeal signs of GER. of at least 15% of sleep. The parameters were: ENT specialists and pediatricians evaluated thoracic and abdominal movement, oronasal flow, the children at the Center for Respiratory Sleep blood oxygen saturation (SpO2), end-tidal carbon

Disorders, ASST Seven Lakes Pediatric Clinic, dioxide (EtCO2), electroencephalogram (EEG), Varese, Italy. electrooculogram (EOG), electrocardiogram (ECG),

Laryngomalacia, breathing and unexplained events in infants 3/8 www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine • vol. 10 • n. 2 • 2021 electromyogram (EMG), audio and video moni The ethics committee of ASST Settelaghi, toring, and position sensor. Measurement of pH Varese, Italy approved the study (approval date or pH impedance was performed in children with 28.08.2018, no. 110/2017). Informed consent was suspected GER. Some centers use daytime testing obtained from the children’s parents or caregivers. in young infants, who will sleep and be fed during the daytime and at night [21]. Results Apnea is classified as OSA or central sleep apnea or both. Based on the mean apnea-hypopnea Patients index (AHI) score, the severity of sleep breathing problems was classified as mild (AHI 1-5 events/h), Of the 448 patients admitted for BRUE or moderate (AHI 6-10 events/hour), and severe (AHI ALTE during the study period, 51/448 (11.4%; > 10 events/h) [22]. 57% female, 43% male) were diagnosed with laryngomalacia. Management and follow-up Symptoms and associated conditions All patients were involved in at least a 2-year follow-up. The follow-up included FFL, dietary- In children with laryngomalacia, inspiratory behavioral counseling, and home cardiorespiratory stridor was reported by parents and established monitoring. Home monitoring enables the detection in 31/51 (60.8%), tirage in 5 (9.8%), and pectus of central apnea and/or intermittent hypoxemia excavatum in 4 (7.8%). Diet-related symptoms [5]. Cardiorespiratory monitoring was performed were seen in 31 children (60.8%); GER was at home with a Getemed Vitaguard® VG 3100 associated with laryngomalacia in 26 (51%) monitor (Getemed, Teltow, Germany) equipped children (Tab. 1). with data recording of thoracic impedance and blood oxygen saturation (pulse oximetry). The Fiberoptic endoscopic findings data were periodically downloaded to the computer and the records were analyzed using VitaWin® The morphological subtypes of laryngomalacia software by an expert physician (LN) for central were: redundant mucosa of the aryepiglottic apnea (> 20 s), desaturation (SpO2 < 90%), and folds with inward collapse on inspiration in bradycardia or tachycardia events. 30/51 (58.8%) (posterolateral collapse), short Home monitoring was performed for at least 6 aryepiglottic folds with curled tubular epiglottis in weeks. If an anomalous event occurred, monitoring 16/51 (31.4%) (complete collapse), and posterior was continued until the event had resolved. Preterm collapse of the epiglottis on inspiration in 5/51 infants with BRUE were monitored up to 43 weeks (9.8%) children (anterior collapse). of post-conceptional age. If symptoms persisted, monitoring was continued for another 6 weeks Type of sleep apnea until complete resolution. Parental compliance was very important because they reported the child’s The 51 patients with laryngomalacia were symptoms over 24 hours. classified according to the most frequent types of

Table 1. Clinical characteristics of the study population (n = 51). Respiratory symptoms No. % Feeding problems No. % OSA and mixed sleep apnea 34 66.7 GER 26 51 Respiratory stridor 31 60.8 Regurgitation and belching 25 49 Tirage 5 9.8 Hiccups 19 37.3 Pectus excavatum 4 7.8 Choking during the meal 14 27.5 Vomiting 12 23.5 Comorbidities No. % Prolonged feeding time, altered suction a 10 19.6 Congenital cardiopathies 10 19.6 ratio, deglutition-respiration, dysphagia Secondary airway lesions 2 3.9 Cough during the meal 9 17.6 a Patent foramen ovale (PFO), interatrial defect (IAD), and interventricular defect (IVD). GER: gastroesophageal reflux; OSA: obstructive sleep apnea.

4/8 Nosetti • De Bernardi • Sica • Latorre • Agosti • Castelnuovo • Cocciolo • Zaffanello Journal of Pediatric and Neonatal Individualized Medicine • vol. 10 • n. 2 • 2021 www.jpnim.com Open Access apneas found on polysomnography. OSA were Evaluation can be done in patients who are more frequent in 20/51 (39.2%), the mixed apneas awake or with the help of anesthesia/sedation were more frequent in 14/51 (27.5%), and the [20, 23]. Evaluation of laryngomalacia with FFL central apneas were more frequent in 17 (33.3%) is more accurate if performed during anesthesia/ children. Based on AHI criteria, sleep disordered sedation than in the patient who is not awake breathing severity was mild in 14 (27.5%), (100% sensitivity and 100% specificity vs. 93% moderate in 30 (58.8%), and severe in 7 (13.7%) sensitivity and 92% specificity, respectively) children. [14]. We evaluated the larynx in conscious children. Vigilance tests are easier to perform for Management extensive screening. We performed morphological classification of the larynx. Other morphological All patients with laryngomalacia followed a classification systems have been proposed such behavioral dietary therapy and 27/51 (52.9%) were as that of Holinger and Konior, which is based on treated with drugs. In particular, 8 (15.7%) children 5 types of laryngomalacia [9]. The University of were treated with histamine (H2) inhibitors or Groningen recently proposed another classification proton pump inhibitors (PPIs) and 19 (37.3%) with of laryngomalacia that distinguishes only 3 purely alginates. Only 1 underwent surgical treatment of dynamic morphological types [19]. However, we the laryngomalacia with sopraglottoplasty, due prefer to use an anatomical classification because to persistent and very noisy breathing. Among it better reflects the endoscopic collapse of the children with respiratory symptoms, 8 (15.7%) supraglottic structures and is more appropriate were treated with nasal wash hypertonic solutions, when deciding which type of supraglottoplasty to nasal drugs (steroids) or oral antibiotics if indicated perform. (upper respiratory tract infections). Although a wide range of conditions can mimic ALTE (e.g., child abuse, congenital anomalies, Follow-up epilepsy, innate errors of metabolism and infec tion), the risk of a recurrent or serious event is The follow-up was carried out in 48/51 extremely low. The rationale to replace the term (94.1%) children. Three children did not come ALTE with that of BRUE was to improve the to the scheduled checkup. In these children, quality of care [3]. Because laryngomalacia has home cardiorespiratory monitoring disclosed a been studied relatively rarely as a cause of ALTE, gradual reduction in the number of desaturation the relationship between the two is still unclear. events. The mean duration of follow-up was 9.8 Furthermore, otolaryngologists are infrequently months (range, 2-31) with a mean healing time of consulted to examine children with ALTE. Airway 12.5 months (range 1-31). Complete resolution abnormalities are considered rare in these children of laryngomalacia was observed in 45 (88.2%) [16], yet our data suggest a possible relationship children. between BRUE and ALTE events, laryngomalacia and OSA. We recently reported that laryngomalacia Discussion (20.3%) and GER (50.8%) were frequently observed in 48 BRUE and 11 OSAS infants (< In total, 1 in 9 children with ALTE or BRUE 1-year-old) with upper respiratory tract obstruction events had laryngomalacia. The anamnestic inter [24]. ENT assessment should be considered in view revealed that 60.8% of these children had at- patients with BRUE and when there is suspicion home respiratory stridor. In a subsequent evaluation, or indirect signs of GER. The Italian guidelines OSA and GER were the most frequent comorbidities recommend second level ENT assessment with associated with laryngomalacia. At the end of home FFL in patients with a history of ALTE/BRUE [5]. follow-up monitoring, respiratory events improved We performed FFL assessment for BRUE in in all children; however, laryngomalacia did not all children < 12 months of age. Laryngeal stridor resolve in 11.8% of children. This is the first report was present in 60% and the incidence of OSA that shows that in infants with ALTE or BRUE there was very high. We found that laryngomalacia is an improvement in laryngomalacia, together with was strongly associated with OSA and that it may sleep disordered breathing reduction. contribute significantly to OSA in these children Diagnosis of laryngomalacia relies on [24]. Digoy et al. reported that laryngomalacia visualization of the larynx during breathing. may contribute significantly to OSA in children >

Laryngomalacia, breathing and unexplained events in infants 5/8 www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine • vol. 10 • n. 2 • 2021

12 months of age [25]. Katz et al. reported that laryngomalacia had baseline abnormal swallowing a body growth defect, hypoxemia, OSAS or other functions [10] and oropharyngeal dysphagia with complications may be present in 20% of children aspiration was the most common diagnosis identified with laryngomalacia [26]. Gonçalves et al. found in infants presenting with ALTEs. Observed clinical that most patients with laryngomalacia also had feedings incorrectly identified 26% of patients as central apnea, while those with other laryngeal having no oropharyngeal dysphagia when in fact problems did not have a predominant type of they had aspiration [33]. Interestingly, in our series apnea [27]. Furthermore, a study carried out at the of children with BRUE (61%), eating disorders were Cincinnati Children’s Hospital Medical Center in present in a mild form, including regurgitation and 2014 confirmed the prevalence of central apnea hiccups. in children with laryngomalacia [28]. In these The overall incidence of GER was 60%. Most children, the laryngeal tone and the sensorimotor of the children with laryngomalacia also had GER integrative function of the larynx were altered. [10, 34]. A systematic review of the literature GER, neurological diseases, and low Apgar scores reported the frequent coexistence of acid reflux and can influence the severity of the disease and its laryngomalacia. Although the definition of reflux clinical course [11]. differed across studies, the overall prevalence was ALTE and BRUE are a challenge for the high (59%). The authors concluded, however, that clinicians. In children with laryngomalacia, OSA the evidence for a causal association was limited without declared history of ALTE or BRUE [34]. In another study, GER was observed in events was recently established as being common 64% of patients and was significantly associated (77.4%) [29]. Recently, in a retrospective review with severe symptoms [35]. GER is frequently of 102 infants with concomitant laryngomalacia encountered in children; it can be an accidental and sleep-related breathing disorders, 55.9% had finding or related to OSA in children with BRUE. only OSA and 44.1% had both central sleep apnea In early infancy (0-18 months), daily GER and OSA that progressively improved over time symptoms were present in more than a quarter of [30]. The comorbid OSA and central sleep apnea children but then declined in frequency and almost improved together with laryngomalacia, according completely disappeared by the age of 12 months to the study by Ratanakorn et al. [30]. All previous [36]. In our study, GER was present in half of the studies did not specifically mention that these patients, more than that reported by Katz et al. children experienced ALTE or BRUE events. In [26], which suggests a possible comorbidity in BRUE patients aged between 1 and 12 months both infants with associated laryngomalacia and BRUE. laryngomalacia and GER were frequently diagnosed Moreover, 23.5% of the children had comorbidities [24]. However, BRUE had more referred-by- attributable to heart disease or secondary upper parents’ sleep symptoms than controls [31]. airway injury. In a previous study involving 110 The relationship between ALTE or BRUE and patients, 27% had comorbidities such as congenital GER is debated. On one hand, the guidelines of the and/or vascular heart disease (1.7%), hereditary or National Institute for Health and Care Excellence perinatal neurological disease (10.9%), and genetic (NICE) confirm that GER is only very rarely the disorders (14.5%) [37]. cause of apnea or ALTE [5]. On the other hand, Home monitoring can detect intermittent apnea respiratory tract infections and GER are reported to and/or hypoxemia, which can compromise the be a more common diagnosis among patients with integrity of the central nervous system. In 1986, the BRUE [32]. U.S. National Institutes of Health (NIH) Consensus The novelty of our study is that, after careful Conference indicated home monitoring in children investigation, laryngomalacia was frequently ob with severe ALTE, idiopathic ALTE, and siblings served in infants with ALTE or BRUE events and of sudden infant death syndrome (SIDS) victims with OSA and GER comorbidities. We cannot prove [38]. This recommendation is included in the that laryngomalacia is a possible cause or risk factor guidelines of the Italian Society of Pediatrics of ALTE or BRUE events. To resolve this issue, [5]. We monitored the BRUE patients for apnea we would need to compare the frequency of this and desaturation and performed FFL to evaluate anomaly in a group of healthy children including progression of laryngomalacia until resolution of the investigation for OSA and GER as possible respiratory events. All patients who completed the comorbidities. However, this investigation is follow-up showed a gradual reduction in the number ethically unthinkable. Therefore, 75.7% children with of night desaturations until complete resolution.

6/8 Nosetti • De Bernardi • Sica • Latorre • Agosti • Castelnuovo • Cocciolo • Zaffanello Journal of Pediatric and Neonatal Individualized Medicine • vol. 10 • n. 2 • 2021 www.jpnim.com Open Access

To our best knowledge, home cardiorespiratory References monitoring is not recommended for the follow-up of children with laryngomalacia alone [7, 9, 13]. 1. Colombo M, Katz ES, Bosco A, Melzi ML, Nosetti L. Brief resolved Children with mild laryngomalacia can be man unexplained events: Retrospective validation of diagnostic criteria aged with close clinical observation. Continuous and risk stratification. Pediatr Pulmonol. 2019;54(1):61-5. monitoring of severe laryngomalacia is necessary, 2. Kahn A; European Society for the Study and Prevention of Infant however, because symptoms may worsen with the Death. Recommended clinical evaluation of infants with an apparent natural course of the disease [6]. Severe signs, life-threatening event. Consensus document of the European Society present in 10% of children with laryngomalacia, for the Study and Prevention of Infant Death, 2003. Eur J Pediatr. are dyspnea with intercostal or xiphoid retraction, 2004;163(2):108-15. OSA, and/or inhalation episodes during meals or 3. Tieder JS, Bonkowsky JL, Etzel RA, Franklin WH, Gremse DA, feeding difficulties [39]. However, laryngomalacia Herman B, Katz ES, Krilov LR, Merritt JL 2nd, Norlin C, Percelay and GER are associated with OSA in young J, Sapién RE, Shiffman RN, Smith MB; Subcommittee on Apparent children (age < 1 year) [24]. Home monitoring Life Threatening Events. Clinical Practice Guideline: Brief has been generally recommended only for patients Resolved Unexplained Events (Formerly Apparent Life-Threatening with a history of ALTE but not for the prevention Events) and Evaluation of Lower-Risk Infants. Pediatrics. of cardiorespiratory events in children with 2019;144(1):e20191360. laryngomalacia alone [39]. 4. Merritt JL 2nd, Quinonez RA, Bonkowsky JL, Franklin WH, In conclusion, FFL demonstrated the presence Gremse DA, Herman BE, Jenny C, Katz ES, Krilov LR, Norlin C, of laryngomalacia in 11.4% of children with a Sapién RE, Tieder JS. A Framework for Evaluation of the Higher- clinical history of high risk for BRUE. BRUE is a Risk Infant After a Brief Resolved Unexplained Event. Pediatrics. heterogeneous condition, in which laryngomalacia 2019;144(2):e20184101. should be considered. The present study is the 5. Piumelli R, Davanzo R, Nassi N, Salvatore S, Arzilli C, Peruzzi M, first to involve children under the age of 12 Agosti M, Palmieri A, Paglietti MG, Nosetti L, Pomo R, De Luca months with BRUE and laryngomalacia and F, Rimini A, De Masi S, Costabel S, Cavarretta V, Cremante A, OSA and GER highly present as a comorbidity. Cardinale F, Cutrera R. Apparent Life-Threatening Events (ALTE): Laryngomalacia should always be evaluated Italian guidelines. Ital J Pediatr. 2017;43(1):111. because, although subclinical in some cases, it can 6. Thompson DM. Laryngomalacia: factors that influence disease be a risk factor or a possible cause of BRUE in severity and outcomes of management. Curr Opin Otolaryngol Head children. Neck Surg. 2010;18(6):564-70. 7. Thorne MC, Garetz SL. Laryngomalacia: Review and Summary of Conclusions Current Clinical Practice in 2015. Paediatr Respir Rev. 2016;17: 3-8. In conclusion, laryngomalacia was diagnosed 8. Richter GT, Wootten CT, Rutter MJ, Thompson DM. Impact of in 1 out of 9 of our children presenting with ALTE supraglottoplasty on aspiration in severe laryngomalacia. Ann Otol or BRUE. FFL in patients with a clinical history Rhinol Laryngol. 2009;118(4):259-66. of ALTE or high risk of BRUE may contribute 9. Holinger LD, Konior RJ. Surgical management of severe to the diagnosis of laryngomalacia. In these chil laryngomalacia. Laryngoscope. 1989;99(2):136-42. dren, sleep apneas and GER were strongly con 10. Simons JP, Greenberg LL, Mehta DK, Fabio A, Maguire RC, comitant conditions. Comorbid sleep disordered Mandell DL. Laryngomalacia and swallowing function in children. breathing was highly present, mainly of moderate Laryngoscope. 2016;126(2):478-84. severity, and GER was diagnosed in half of these 11. Thompson DM. Abnormal sensorimotor integrative function of patients. Eating disorders were present in more the larynx in congenital laryngomalacia: a new theory of etiology. than half of these patients. The interrelation Laryngoscope. 2007;117(6 Pt 2 Suppl 114):1-33. ship between laryngomalacia, sleep apneas and 12. Dobbie AM, White DR. Laryngomalacia. Pediatr Clin North Am. BRUE requires further studies to confirm our obser- 2013;60(4):893-902. vations. 13. Ayari S, Aubertin G, Girschig H, Van Den Abbeele T, Denoyelle F, Couloignier V, Mondain M. Management of laryngomala Declaration of interest cia. Eur Ann Otorhinolaryngol Head Neck Dis. 2013;130(1): 15-21. The Authors have no conflicts of interest to declare. This research did 14. Sivan Y, Ben-Ari J, Soferman R, DeRowe A. Diagnosis of not receive any specific grant from funding agencies in the public, laryngomalacia by fiberoptic endoscopy: awake compared with commercial, or not-for-profit sectors. anesthesia-aided technique. Chest. 2006;130(5):1412-8.

Laryngomalacia, breathing and unexplained events in infants 7/8 www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine • vol. 10 • n. 2 • 2021

15. Okada K, Miyako M, Honma S, Wakabayashi Y, Sugihara S, on children with laryngopathies. Braz J Otorhinolaryngol. Osawa M. Discharge diagnoses in infants with apparent life- 2006;72(2):187-92. threatening event. Pediatr Int. 2003;45(5):560-3. 28. Tanphaichitr A, Tanphaichitr P, Apiwattanasawee P, Brockbank 16. Willis MW, Bonkowsky JL, Srivastava R, Grimmer JF. Usefulness J, Rutter MJ, Simakajornboon N. Prevalence and risk factors for of airway evaluation in infants initially seen with an apparent central sleep apnea in infants with laryngomalacia. Otolaryngol life-threatening event. Arch Otolaryngol Head Neck Surg. Head Neck Surg. 2014;150(4):677-83. 2011;137(4):359-62. 29. Verkest V, Verhulst S, Van Hoorenbeeck K, Vanderveken O, Saldien 17. Svystun O, Johannsen W, Persad R, Turner JM, Majaesic C, El- V, Boudewyns A. Prevalence of obstructive sleep apnea in children Hakim H. Dysphagia in healthy children: Characteristics and with laryngomalacia and value of polysomnography in treatment management of a consecutive cohort at a tertiary centre. Int J decisions. Int J Pediatr Otorhinolaryngol. 2020;137:110255. Pediatr Otorhinolaryngol. 2017;99:54-9. 30. Ratanakorn W, Brockbank J, Ishman S, Tadesse DG, Hossain 18. Roger G, Denoyelle F, Triglia JM, Garabedian EN. Severe MM, Simakajornboon N. The maturation changes of sleep-related laryngomalacia: surgical indications and results in 115 patients. respiratory abnormalities in infants with laryngomalacia. J Clin Laryngoscope. 1995;105(10):1111-7. Sleep Med. 2021;17(4):767-77. 19. van der Heijden M, Dikkers FG, Halmos GB. The Groningen 31. Nosetti L, Angriman M, Zaffanello M, Salvatore S, Riggi laryngomalacia classification system – based on systematic review L, Niespolo AC, Salvatoni A, Agosti M. Increased parental and dynamic airway changes. Pediatr Pulmonol. 2015;50(12): perception of sleep disordered breathing in a cohort of infants 1368-73. with ALTE/BRUE events. Minerva Pediatr. 2018 Oct 4. [Epub 20. Kelley PE. Surgical treatment of laryngomalacia. Operative ahead of print]. Techniques in Otolaryngology – Head and Neck Surgery. 32. Alhaboob AA. Clinical Characteristics and Outcomes of Patients 2005;16(3):198-202. Admitted with Brief Resolved Unexplained Events to a Tertiary 21. Cielo CM. Question 3: What are the indications for and challenges Care Pediatric Intensive Care Unit. Cureus. 2020;12(6):e8664. in performing polysomnography in infants? Paediatr Respir Rev. 33. Duncan DR, Amirault J, Mitchell PD, Larson K, Rosen 2019;30:27-9. RL. Oropharyngeal Dysphagia Is Strongly Correlated With 22. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, Apparent Life-Threatening Events. J Pediatr Gastroenterol Nutr. Marcus CL, Mehra R, Parthasarathy S, Quan SF, Redline S, Strohl 2017;65(2):168-72. KP, Davidson Ward SL, Tangredi MM; American Academy of 34. Hartl TT, Chadha NK. A systematic review of laryngomalacia and Sleep Medicine. Rules for scoring respiratory events in sleep: acid reflux. Otolaryngol Head Neck Surg. 2012;147(4):619-26. update of the 2007 AASM Manual for the Scoring of Sleep and 35. Giannoni C, Sulek M, Friedman EM, Duncan NO 3rd. Associated Events. Deliberations of the Sleep Apnea Definitions Gastroesophageal reflux association with laryngomalacia: a Task Force of the American Academy of Sleep Medicine. J Clin prospective study. Int J Pediatr Otorhinolaryngol. 1998;43(1): Sleep Med. 2012;8(5):597-619. 11-20. 23. Whymark AD, Clement WA, Kubba H, Geddes NK. Laser 36. Singendonk M, Goudswaard E, Langendam M, van Wijk M, epiglottopexy for laryngomalacia: 10 years’ experience in the west of van Etten-Jamaludin F, Benninga M, Tabbers M. Prevalence Scotland. Arch Otolaryngol Head Neck Surg. 2006;132(9):978-82. of Gastroesophageal Reflux Disease Symptoms in Infants and 24. Nosetti L, Zaffanello M, De Bernardi F, Piacentini G, Roberto Children: A Systematic Review. J Pediatr Gastroenterol Nutr. G, Salvatore S, Simoncini D, Pietrobelli A, Agosti M. Age 2019;68(6):811-7. and Upper Airway Obstruction: A Challenge to the Clinical 37. Kusak B, Cichocka-Jarosz E, Jedynak-Wasowicz U, Lis G. Types Approach in Pediatric Patients. Int J Environ Res Public Health. of laryngomalacia in children: interrelationship between clinical 2020;17(10):3531. course and comorbid conditions. Eur Arch Otorhinolaryngol. 25. Digoy GP, Shukry M, Stoner JA. Sleep apnea in children with 2017;274(3):1577-83. laryngomalacia: diagnosis via sedated endoscopy and objective 38. [No authors listed]. National Institutes of Health Consensus outcomes after supraglottoplasty. Otolaryngol Head Neck Surg. Development Conference on Infantile Apnea and Home Monitoring, 2012;147(3):544-50. Sept 29 to Oct 1, 1986. Pediatrics. 1987;79(2):292-9. 26. Katz ES, Mitchell RB, D’Ambrosio CM. Obstructive sleep apnea in 39. Ayari S, Aubertin G, Girschig H, Van Den Abbeele T, Mondain infants. Am J Respir Crit Care Med. 2012;185(8):805-16. M. Pathophysiology and diagnostic approach to laryngomalacia 27. Gonçalves MT, Sato J, Avelino MA, Pizarro GU, Moreira GA, in infants. Eur Ann Otorhinolaryngol Head Neck Dis. Hallinan MP, Fujita RR, Wechx LL. Polisomnographic findings 2012;129(5):257-63.

8/8 Nosetti • De Bernardi • Sica • Latorre • Agosti • Castelnuovo • Cocciolo • Zaffanello